rs7315124

Positions:

• chr12-5991805-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):​c.6798+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,613,308 control chromosomes in the GnomAD database, including 544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (198 hom., cov: 33)
  • Exomes 𝑓: 0.013 (346 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.173

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-5991805-G-A is Benign according to our data. Variant chr12-5991805-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5991805-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.6798+14C>T		intron_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.6798+14C>T		intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.6798+14C>T		intron_variant		1	NM_000552.5	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4928 AN: 152172 Hom.: 197 Cov.: 33

Gnomad AFR AF: 0.0893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00820

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0187 AC: 4694 AN: 251040 Hom.: 127 AF XY: 0.0193 AC XY: 2616 AN XY: 135714

Gnomad AFR exome AF: 0.0880

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0487

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00830

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0127 AC: 18579 AN: 1461018 Hom.: 346 Cov.: 32 AF XY: 0.0138 AC XY: 10031 AN XY: 726852

Gnomad4 AFR exome AF: 0.0933

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.0243

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0482

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.00791

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0324 AC: 4936 AN: 152290 Hom.: 198 Cov.: 33 AF XY: 0.0318 AC XY: 2369 AN XY: 74480

Gnomad4 AFR AF: 0.0893

Gnomad4 AMR AF: 0.0193

Gnomad4 ASJ AF: 0.0279

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0424

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00820

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0226 Hom.: 21

Bravo AF: 0.0353

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

von Willebrand disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

von Willebrand disease type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary von Willebrand disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7315124; hg19: chr12-6100971;